Gene-Based Therapies for Inherited Corneal Disease

Corneal dystrophies (CDs) are a group of rare progressive genetic diseases, including those inherited in an autosomal dominant, autosomal recessive, and sex-linked fashion.

They may occur due to dysgenesis, or even as a result of foreign proteins accumulating in one or more of the five layers of the cornea.

Overview of corneal dystrophies

Corneal dystrophies affect both men and women equally, among all ages, except Fuchs’ corneal dystrophy, which is four times more likely to affect women than men.³ Although the incidence rate of CDs is unknown,³ a range of visual acuities may manifest due to the variation in severity between dystrophies and within certain dystrophies as well. Patients may be asymptomatic, have complaints of blurred vision, discomfort, dryness, light sensitivity, and, in some cases, legal blindness.^3-4

Over 20 CD subtypes exist and are classified according to which corneal layer is affected. Most corneal dystrophies usually affect both eyes, progress slowly, and do not involve other body systems/organs.^1-4 Although there is no cure for corneal dystrophies, treatments such as glasses, contact lenses, keratectomy, corneal transplants, and/or gene-based therapies may slow down disease progression and improve symptoms.⁴

Diagnostic tools to evaluate corneal dystrophies

CDs are incidentally found during routine eye exams and further evaluated with carefully recorded patient histories and slit lamp examinations. Some CDs can be detected prior to symptom development with molecular genetic testing.^1,3-4

Download the Corneal Dystrophy Categories and Subgroups Cheat Sheet here!

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Corneal Dystrophy Categories and Subgroups At-A-Glance

This cheat sheet outlines inherited corneal dystrophies ophthalmologists may encounter, featuring key characteristics, inheritance patterns, and gene mutation locations.

Classification of corneal dystrophies

Corneal dystrophies are classified into one of three subgroups, depending on the corneal layer affected: anterior, stromal, and posterior.¹ These are further divided into subgroups, each of which has its own characteristics.

Anterior corneal dystrophies

Anterior CDs involve the epithelium and Bowman’s membrane. The epithelium is the outermost layer, and the Bowman membrane is the second layer that protects the eye due to its tough and difficult-to-penetrate qualities.³ Unless noted otherwise, these dystrophies are inherited in an autosomal dominant fashion.

Epithelial Basement Membrane Dystrophy: Fairly common and characterized by the development of microcysts in histopathology. It is also known as map-dot-fingerprint dystrophy and Cogan microcystic dystrophy.³
Meesmann Corneal Dystrophy: Very rare and is characterized by the development of clusters of multiple, small, clear cysts, roughly similar in size. It is also referred to as juvenile epithelial dystrophy.³
Lisch Corneal Dystrophy: Characterized by band-shaped or whorled patterned cysts that appear in clusters.³ Lisch corneal dystrophy is inherited in an X-linked dominant pattern.
Reis-Buckler Corneal Dystrophy: Also known as granular corneal dystrophy type III, affects Bowman’s membrane. It is characterized by progressive membrane scarring, opacity, and, in serious cases, corneal erosion. It is also referred to as corneal dystrophy of Bowman layer type I.³
Thiel-Behnke Corneal Dystrophy: As it also affects the Bowman membrane, it may be extremely difficult to discern from Reis-Buckler corneal dystrophy. Due to the honeycomb-like appearance of the lesions (on histopathology slides), this CD is also known as honeycomb corneal dystrophy or corneal dystrophy of Bowman layer type II.³

Stromal corneal dystrophies

Stromal CDs involve the corneal stroma, the thickest corneal layer that is composed of water, collagen fibers, and other connective tissues. These components provide strength, elasticity, and visual clarity.³ Stromal CDs may further progress into other corneal layers. Unless noted otherwise, these dystrophies are inherited in an autosomal dominant fashion.

Granular Corneal Dystrophy Type I: Characterized by granule development that may eventually coalesce into larger lesions and potentially erosions. These granules can resemble breadcrumbs on slit lamp exam.³
Granular Corneal Dystrophy Type II: Also known as Avellino corneal dystrophy, is characterized by lesions that appear to be a hybrid of granular corneal dystrophy type I lesions and lattice corneal dystrophy lesions.
Lattice Corneal Dystrophies, Types I and II: Characterized by branching lesions that overlap in a lattice pattern. This CD is more likely to recur in corneal grafts.³
Gelatinous Drop-Like Corneal Dystrophy: Also known as familial subepithelial corneal dystrophy. Gelatinous amyloid masses accumulate beneath the corneal epithelium.³
Macular Corneal Dystrophy: Known as Groenouw dystrophy type II, occurs between ages 3 to 9 and results in stromal clouding and painful recurrent erosions.
Schnyder Crystalline Corneal Dystrophy: Results due to fat or cholesterol crystals in the cornea.³ This rare dystrophy inheritance pattern is autosomal recessive.

Posterior corneal dystrophies

Posterior CDs affect the endothelium and the Descemet membrane, or the innermost layers of the cornea. The Descemet membrane is a thin inner layer that provides protection, and the endothelium is the innermost layer composed of cells that normally pump excess water out of the cornea.³ Posterior CDs may further spread and affect all other layers. Unless noted otherwise, these dystrophy patterns are autosomal dominant.

Fuchs’ Endothelial Dystrophy: Characterized by the loss of endothelial cells, which normally pump water out of the corneal tissue. As a result, the cornea is more likely to become edematous, with the potential for corneal bullae and scarring.³
Posterior Polymorphous Dystrophy: Rare but may potentially present at birth. It is characterized by lesions on the endothelium and may lead to increased intraocular pressure.³
Congenital Hereditary Corneal Dystrophies (CHED), Types I and II: Differ in when they present and how they are genetically acquired. Type I is inherited in an autosomal dominant manner and is characterized by corneal edema, pain, and clear corneas at birth, which later on become opaque in infancy.³ Type II is more common and inherited autosomal recessively and is characterized by corneal edema and opacity at birth. Nystagmus may occur with Type II.³

Current treatments for corneal dystrophies

Corneal dystrophy treatment includes eye drops, ointments, lasers, and keratoplasty. Accompanying corneal erosions may be treated via eye drops, ointments, antibiotics, and/or soft bandaging contact lenses. With recurrent erosions, recalcitrant to medical therapy, superficial keratectomy, or excimer laser therapy (phototherapeutic keratectomy) may be considered. Genetic counseling may further benefit the patient and their families for future planning.³

Current transplant management can be incredibly successful but does pose challenges of the possible need to repeat treatments, elaborate surgeries, cornea donor shortages, and graft rejections.⁵ Genetic therapies prove to be an important field to mine through as they can overcome the challenges of corneal transplants in CD. As Thomas Ciulla, MD, MBA, stated in 2019, key clinical trials have been promising in introducing and expanding the use of gene therapy in ophthalmology.⁶

What is gene-based therapy?

Gene therapy is a toolset to modify an individual’s genes to either treat or cure a disease. Key corneal characteristics are advantageous for corneal disease treatment with gene therapy.⁷ The cornea has a simple histological structure, is easily accessible to examine and manipulate, can be maintained in ex vivo culture for weeks,⁷ and the anterior chamber confers immune privilege.^5,7-8

Additionally, the cornea is advantageous due to its transparency, avascularity, and available advanced imaging/surgical techniques.^5,8 A few drawbacks to corneal-based gene therapy confer barriers such as strong resistance against external gene delivery via topical transfer due to tear flow and durable epithelial tight junctions.^5,8

Current gene-based treatments for corneal dystrophies

Gene therapy involves three strategies in order to bring about therapeutic effects: gene supplementation, gene silencing, and gene editing.^5-6,9

Gene supplementation is simple and one of the most widely used methods,^5,9 as it involves delivering a functional wild-type copy of the mutated gene in order to restore the gene function and correct the defect.^5-6,9 This method is especially useful in autosomal recessive inherited CDs due to the nature of the loss-of-function gene.
Gene silencing involves the delivery of an interfering molecule, i.e., antisense RNA, to inactivate the faulty gene product that is causing the disease pathogenicity.^5-6,9
Gene editing involves changing the hosts’ genetic sequence in order to correct the underlying cause of the CD and restore normal ocular function.^5-6,9

In the relatively new field of genetic engineering in ophthalmology, the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has been promising for editing in CDs.⁵ Gene editing in the cornea is possible ex vivo and in vivo with CRISPR, and due to the targeting allele-specific mutations with this molecular vehicle, autosomal dominant CDs can be directly managed by gene sequence deletions.⁵

Various CRISPR-based studies are currently underway for corneal dystrophies, with the system being used specifically in endothelial corneal cells for in vitro and rat models. Per Salman et al., there are currently seven individual PMID reference numbers attached to studies for targeted gene therapy using CRISPR in corneal diseases or various types, including granular corneal dystrophy, Meesmann’s epithelial corneal dystrophy, lattice corneal dystrophy (type I), and Fuchs' endothelial corneal dystrophy.⁵

Conclusion

Corneal dystrophies (CDs) are a group of rare progressive genetic diseases resulting in a spectrum of symptoms, depending on the condition. Although asymptomatic in some, CDs can be severely detrimental, with some eventually losing their vision.

Current treatments focus on symptom management and/or keratoplasties; however, the disadvantages that accompany these treatments prove to be difficult. Thus, this review states why gene therapy is an important field in ophthalmological disease management.